Frank A

References (4)

Title : Benzophenone Derivatives with Histamine H(3) Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease - Godyn_2022_Molecules_28_
Author(s) : Godyn J , Zareba P , Stary D , Kaleta M , Kuder KJ , Latacz G , Mogilski S , Reiner-Link D , Frank A , Doroz-Plonka A , Olejarz-Maciej A , Sudol-Talaj S , Nolte T , Handzlik J , Stark H , Wieckowska A , Malawska B , Kiec-Kononowicz K , Lazewska D , Bajda M
Ref : Molecules , 28 : , 2022
Abstract : The multitarget-directed ligands demonstrating affinity to histamine H(3) receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H(3)R (K(i) = 8 nM) and significant inhibitory activity toward BuChE (IC(50) = 172 nM and 1.16 microM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (P(e)) of 6.3 x 10(-6) cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED(50) = 20.9 mg/kg) and inflammatory (ED(50) = 17.5 mg/kg) pain.
ESTHER : Godyn_2022_Molecules_28_
PubMedSearch : Godyn_2022_Molecules_28_
PubMedID: 36615435

Title : Cyanobiphenyls: Novel H(3) receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease - Godyn_2021_Bioorg.Chem_114_105129
Author(s) : Godyn J , Zareba P , aewska D , Stary D , Reiner-Link D , Frank A , Latacz G , Mogilski S , Kaleta M , Doroz-Plonka A , Lubelska A , Honkisz-Orzechowska E , Olejarz-Maciej A , Handzlik J , Stark H , Kiec-Kononowicz K , Malawska B , Bajda M
Ref : Bioorg Chem , 114 :105129 , 2021
Abstract : Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of K(i) values) for human histamine H(3) receptors (hH(3)R) and good nonselective inhibitory potency (micromolar range of IC(50) values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH(3)R/eeAChE/eqBuChE/hMAO B ligand (5: hH(3)R K(i) = 9.2 nM; eeAChE IC(50) = 2.63 microM; eqBuChE IC(50) = 1.30 microM; hMAO B IC(50) = 0.60 microM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
ESTHER : Godyn_2021_Bioorg.Chem_114_105129
PubMedSearch : Godyn_2021_Bioorg.Chem_114_105129
PubMedID: 34217977

Title : Biphenylalkoxyamine Derivatives-Histamine H(3) Receptor Ligands with Butyrylcholinesterase Inhibitory Activity - Lazewska_2021_Molecules_26_
Author(s) : Lazewska D , Zareba P , Godyn J , Doroz-Plonka A , Frank A , Reiner-Link D , Bajda M , Stary D , Mogilski S , Olejarz-Maciej A , Kaleta M , Stark H , Malawska B , Kiec-Kononowicz K
Ref : Molecules , 26 : , 2021
Abstract : Neurodegenerative diseases, e.g., Alzheimer's disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H(3) receptors (H(3)Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H(3)R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H(3)R ligands. Most of these compounds show high affinity for human H(3)R (K(i) < 150 nM) and submicromolar inhibition of BuChE (IC(50) < 1 microM). Among all the tested compounds, 19 (E153, 1-(5-([1,1'-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H(3)R, with a K(i) value of 33.9 nM, and for equine serum BuChE, with an IC(50) of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC(50) of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.
ESTHER : Lazewska_2021_Molecules_26_
PubMedSearch : Lazewska_2021_Molecules_26_
PubMedID: 34208297

Title : Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease - Olazaran_2004_Neurology_63_2348
Author(s) : Olazaran J , Muniz R , Reisberg B , Pena-Casanova J , Del Ser T , Cruz-Jentoft AJ , Serrano P , Navarro E , Garcia de la Rocha ML , Frank A , Galiano M , Fernandez-Bullido Y , Serra JA , Gonzalez-Salvador MT , Sevilla C
Ref : Neurology , 63 :2348 , 2004
Abstract : OBJECTIVE: To evaluate the efficacy of a cognitive-motor program in patients with early Alzheimer disease (AD) who are treated with a cholinesterase inhibitor (ChEI).
METHODS: Patients with mild cognitive impairment (MCI) (12), mild AD (48), and moderate AD (24) (Global Deterioration Scale stages 3, 4, and 5) were randomized to receive psychosocial support plus cognitive-motor intervention (experimental group) or psychosocial support alone (control group). Cognitive-motor intervention (CMI) consisted of a 1-year structured program of 103 sessions of cognitive exercises, plus social and psychomotor activities. The primary efficacy measure was the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary efficacy measures were the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Geriatric Depression Scale. Evaluations were conducted at 1, 3, 6, and 12 months by blinded evaluators.
RESULTS: Patients in the CMI group maintained cognitive status at month 6, whereas patients in the control group had significantly declined at that time. Cognitive response was higher in the patients with fewer years of formal education. In addition, more patients in the experimental group maintained or improved their affective status at month 12 (experimental group, 75%; control group, 47%; p = 0.017).
CONCLUSIONS: A long-term CMI in ChEI-treated early Alzheimer disease patients produced additional mood and cognitive benefits.
ESTHER : Olazaran_2004_Neurology_63_2348
PubMedSearch : Olazaran_2004_Neurology_63_2348
PubMedID: 15623698